Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.

A mild subtype of autosomal recessive limb girdle muscular dystrophy characterized by slowly progressive proximal muscle weakness and wasting of the pelvic and shoulder girdles with onset that usually occurs during the second or third decade of life. Clinical presentation is variable and can include calf psuedohypertrophy, joint contractures, scapular winging, muscle cramping and/or facial and respiratory muscle involvement.

Facioscapulohumeral muscular dystrophy (FSHD) typically presents with weakness of the facial muscles, the stabilizers of the scapula, or the dorsiflexors of the foot. Severity is highly variable. Weakness is slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened.

Autosomal dominant limb-girdle muscular dystrophy-3 (LGMDD3) is characterized by slowly progressive proximal muscle weakness affecting the upper and lower limbs. Onset is usually in adulthood, but can occur during the teenage years. Affected individuals may also develop cataracts before age 50 (summary by Vieira et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).

Alpha-B crystallin-related myofibrillar myopathy is an autosomal dominant muscular disorder characterized by adult onset of progressive muscle weakness affecting both the proximal and distal muscles and associated with respiratory insufficiency, cardiomyopathy, and cataracts. There is phenotypic variability both within and between families (Fardeau et al., 1978; Selcen and Engel, 2003). A homozygous founder mutation in the CRYAB gene has been identified in Canadian aboriginal infants of Cree origin who have a severe fatal infantile hypertonic form of myofibrillar myopathy; see 613869. For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

Autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2) is a myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients. Affected individuals also have distal muscle weakness of the hands and lower leg muscles. There is variability in presentation and progression. Some patients present in early childhood with mildly delayed walking and difficulty running and jumping, whereas others present as adults with mainly pelvic-girdle weakness. Patients with early onset tend to have a more severe disorder, and may develop contractures, loss of independent ambulation, and respiratory insufficiency. Muscle biopsy shows dystrophic changes with abnormal nuclei, rimmed vacuoles, and filamentous inclusions (summary by Melia et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).

Autosomal dominant myosin storage congenital myopathy-7A (CMYO7A) is a skeletal muscle disorder with wide phenotypic variability. The age at symptom onset can range from early childhood to late adulthood. Affected individuals have proximal muscle weakness affecting the upper and lower limbs and distal muscle weakness of the lower limbs, resulting in gait difficulties and scapular winging (scapuloperoneal myopathy). Additional features may include thin habitus, high-arched palate, foot drop, pes cavus, calf pseudohypertrophy, and decreased reflexes. The severity is also variable: some patients develop respiratory insufficiency, joint contractures, and scoliosis in the first decades, whereas others are clinically unaffected, but show subtle signs of the disorder on examination. Serum creatine kinase may be normal or elevated. The disease is usually slowly progressive and most patients remain ambulatory. Skeletal muscle biopsy can show different abnormalities, including hyaline bodies, type 1 fiber predominance, congenital fiber-type disproportion (CFTD), and nonspecific myopathic changes with myofibrillar disarray. Intrafamilial variability is common (Dye et al., 2006; Pegoraro et al., 2007; review by Tajsharghi and Oldfors, 2013). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.

MDGDC5 is an autosomal recessive muscular dystrophy characterized by variable age at onset, normal cognition, and no structural brain changes (Brockington et al., 2001). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2006). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).

Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. The phenotype varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.

The spectrum of ANO5 muscle disease is a continuum that ranges from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. The most typical presentation is limb-girdle muscular dystrophy type 2L (LGMD2L) with late-onset proximal lower-limb weakness in the fourth or fifth decade (range 15-70 years). Less common is Miyoshi-like disease (Miyoshi muscular dystrophy 3) with early-adult-onset calf distal myopathy (around age 20 years). Incidental hyperCKemia may be present even earlier. Initial symptoms are walking difficulties, reduced sports performance, and difficulties in standing on toes as well as nonspecific exercise myalgia and/or burning sensation in the calf muscles. Muscle weakness and atrophy are frequently asymmetric. Cardiac findings can include cardiomyopathy and arrhythmias and/or left ventricular dysfunction. Bulbar or respiratory symptoms have not been reported. Females have milder disease manifestations than males. Disease progression is slow in both the LGMD and distal forms; ambulation is preserved until very late in the disease course. Life span is normal.

Autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) is characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA (mtDNA) deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression (summary by Ronchi et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).

Polyglucosan body myopathy-2 is an autosomal recessive disorder characterized by proximal muscle weakness of the lower limbs resulting in gait disturbances. Some patients also have involvement of the upper limbs and/or distal muscle weakness. The age at onset is highly variable, and the disorder is slowly progressive. Muscle biopsy shows accumulation of polyglucosan, which contains abnormally long and poorly branched glucosyl chains and is variably resistant to digestion by alpha-amylase (summary by Malfatti et al., 2014). For a discussion of genetic heterogeneity of PGBM, see PGBM1 (615895).

Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with IBMPFD.

Autosomal dominant limb-girdle muscular dystrophy is characterized by proximal and/or distal muscle weakness and atrophy. The age at onset is variable and can range from the first to the sixth decade, although later onset is less common. Most patients present with proximal muscle weakness that progresses to distal involvement, but some can present with distal impairment. The severity is variable: patients with a more severe phenotype can lose ambulation after several decades and have facial weakness with bulbar and respiratory involvement. Muscle biopsy shows dystrophic changes with protein aggregates, myofibrillar degeneration, and rimmed vacuoles (summary by Ruggieri et al., 2015). Genetic Heterogeneity of Autosomal Dominant Limb-Girdle Muscular Dystrophy Other forms of autosomal dominant LGMD include LGMDD2 (608423), previously LGMD1F, caused by mutation in the TNPO3 gene (610032) on chromosome 7q32; LGMDD3 (609115), previously LGMD1G, caused by mutation in the HNRNPDL gene (607137) on chromosome 4q21; and LGMDD4 (618129), previously LGMD1I, caused by mutation in the CAPN3 gene (114240) on chromosome 15q15. For a discussion of autosomal recessive LGMD, see 253600.

Autosomal dominant nemaline myopathy-5C (NEM5C) is a relatively mild skeletal muscle disorder with wide clinical variability, even within families. Affected individuals develop symptoms of muscle weakness in the first or second decades; those with earlier onset tend to have a more severe disease course. Features include difficulty walking on the heels, waddling gait, proximal muscle weakness affecting the upper and lower limbs, and Gowers sign. Additional features may include myopathic facies, high-arched palate, scoliosis or kyphosis, and ankle weakness. Patients remain ambulatory into late adulthood. Skeletal muscle biopsy shows hypotrophy of type 1 fibers, hypertrophy of type 2 fibers, fiber size variation, and myofibrillar disorganization. Nemaline rods in type 1 fibers are often observed, but are not always present (Konersman et al., 2017; Holling et al., 2022). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).

Ullrich congenital muscular dystrophy-1 (UCMD1) is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (summary by Kirschner, 2013). For general phenotypic information and a discussion of genetic heterogeneity of Ullrich congenital muscular dystrophy, see UCMD1A (254090).